Synergistic effect of APOE genotype and obesity in CNS inflammation and risk of Alzheimer's disease

APOE 基因型和肥胖对中枢神经系统炎症和阿尔茨海默病风险的协同作用

• 批准号: 10300827
• 负责人: G WILLIAM REBECK
• 金额: $ 23.4万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300827
• 关键词: Address; Advanced Glycosylation End Products; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Anti-Inflammatory Agents; Apolipoprotein E; Applications Grants; Area; Behavioral Assay; Biological Assay; Biological Markers; Blood; Brain; Cells; Chronic; Complex; Data; Diabetes Mellitus; Diet; Disease; ERG gene; Early Intervention; Environment; Environmental Exposure; Environmental Risk Factor; FOS gene; Female; Future; Genes; Genetic; Genotype; High Density Lipoproteins; High Fat Diet; Human; I-kappa B Proteins; Immediate-Early Genes; Immunofluorescence Immunologic; Impaired cognition; In Situ Hybridization; Individual; Inflammation; Inflammatory; Intervention; Knock-in; Knock-in Mouse; Lesion; Life; Macronutrients Nutrition; Measures; Messenger RNA; Metabolic; Metabolic syndrome; Metformin; Microglia; Modeling; Morphology; Mus; Nervous System Trauma; Neuroglia; Obesity; Pathologic; Pathway interactions; Penetrance; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Plasma; Population; Pre-Clinical Model; Property; Protein Isoforms; Proteins; Risk; Risk Factors; Rodent Model; Sampling; Severities; Signal Pathway; Standardization; Structure; Subgroup; Technology; Testing; Time; Transcript; Traumatic Brain Injury; aging brain; apolipoprotein E-4; base; cell motility; comorbidity; density; driving force; experience; functional outcomes; genetic risk factor; genotypic sex; high risk; in vivo; inflammatory marker; male; mimetics; mouse model; nano-string; neurochemistry; neuroinflammation; normal aging; personalized medicine; response; sex; western diet

PROJECT SUMMARY We have previously pursued the hypothesis that APOE genotype alters normal brain neurochemistry and structure early in life, generating an environment that alters the risk of Alzheimer’s Disease (AD) with aging. Studies with APOE knock-in mice have demonstrated that APOE genotype affects neuroinflammation in response to various neurological injuries in an isoform-specific manner, with apoE4 displaying the least anti- inflammatory activity. Inflammation is also a consequence of several environmental risk factors for AD, such as traumatic brain injury, obesity, and metabolic syndrome. Obesity is the strongest environmental risk factor for AD. With 14% of the US population being APOE4 carriers and 35% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors synergize. Sex is also a critical variable in the risk of cognitive impairments, with females at significantly higher risk. Thus, the risk of AD depends on a complex set of connections between genetic, environmental, and sex effects. This project aims to analyze these interactions in healthy rodent models, thus providing early disease targets that could be use as markers of AD risk and as targets for disease intervention. Aim 1 will determine robust markers of neuroinflammation in APOE3 and APOE4 male and female mice after experiencing chronic peripheral inflammation induced by diet. We will test our hypothesis that specific neuroinflammatory pathways will be coordinately affected by these three AD risk factors. We have begun to identify neuroinflammatory pathways through non-directed transcript analysis, and we will test the rigor of those findings through qPCR. We will further refine specific neuroinflammatory pathways using immunofluorescence, in situ hybridization analyses, and kinase measures. Finally, we will define inflammatory cell responses by defining the density, morphology, and motility of the microglia using our model of CX3CR1GFP/+ mice on APOE3 and APOE4 knock-in backgrounds. Aim 2 will determine the effects of two safe, anti-inflammatory drugs on CNS inflammation markers in the subgroups of most affected APOE female and male mice. We will treat APOE3 and APOE4 mice on a high fat diet with metformin (a diabetes treatment) or 4F peptide (promoting high density lipoproteins). We will test our hypothesis that safe anti-inflammatory drugs could reduce the neuroinflammatory pathways most consistent with AD risk factors. These studies will refine the pathways identified in Aim 1, and further those findings by addressing whether there are functional CNS consequences of these treatments through behavioral assays. Furthermore, we will test whether any inflammation pathways identified in CNS correlate with effects in the blood using assays on plasma samples. By the end of this R21 study, we will have identified a subset of neuroinflammatory molecules that could be use as early markers of AD risk and defined whether anti- inflammatory approaches will be useful in personalized medicine approaches taking APOE genotype, diet, and sex into account.

项目概要 我们之前提出了 APOE 基因型改变正常大脑神经化学的假设，并且 生命早期的结构，产生一个环境，随着年龄的增长，改变阿尔茨海默氏病（AD）的风险。 对 APOE 敲入小鼠的研究表明，APOE 基因型影响神经炎症 以异构体特异性方式对各种神经损伤做出反应，apoE4 表现出最少的抗- 炎症活动。炎症也是 AD 的多种环境风险因素的结果，例如 外伤性脑损伤、肥胖和代谢综合征。肥胖是最强的环境风险因素 广告。 14% 的美国人口是 APOE4 携带者，35% 的人口患有肥胖症， 了解这两种常见的 AD 风险因素如何协同作用极其重要。性也很关键 认知障碍的风险存在差异，其中女性的风险明显更高。因此，AD 的风险取决于 遗传、环境和性别影响之间的一系列复杂联系。该项目旨在分析 健康啮齿动物模型中的这些相互作用，从而提供可用作标记的早期疾病目标 AD 风险并作为疾病干预的目标。目标 1 将确定神经炎症的稳健标志物 APOE3 和 APOE4 雄性和雌性小鼠经历饮食引起的慢性外周炎症后。 我们将检验我们的假设，即特定的神经炎症途径将受到以下因素的协调影响： 这三个 AD 危险因素。我们已经开始通过非定向来识别神经炎症途径 转录本分析，我们将通过 qPCR 测试这些结果的严谨性。我们将进一步细化具体 使用免疫荧光、原位杂交分析和激酶测量的神经炎症途径。 最后，我们将通过定义炎症细胞的密度、形态和运动性来定义炎症细胞反应。 使用我们的 CX3CR1GFP/+ 小鼠模型在 APOE3 和 APOE4 敲入背景下观察小胶质细胞。目标2将 确定两种安全的抗炎药物对亚组中枢神经系统炎症标志物的影响 APOE 雌性和雄性小鼠受影响最大。我们将用高脂肪饮食治疗 APOE3 和 APOE4 小鼠 二甲双胍（一种糖尿病治疗药物）或 4F 肽（促进高密度脂蛋白）。我们将测试我们的 假设安全的抗炎药物可以最大程度地减少神经炎症途径 与 AD 危险因素一致。这些研究将完善目标 1 中确定的途径，并进一步推进这些途径 通过行为研究来解决这些治疗是否对中枢神经系统功能产生影响 化验。此外，我们将测试中枢神经系统中发现的任何炎症途径是否与 使用血浆样本检测来检测血液。到本 R21 研究结束时，我们将确定一个子集 神经炎症分子可用作 AD 风险的早期标志物，并确定是否可以抗 炎症方法将有助于采用 APOE 基因型、饮食和 考虑到性别。